Quality of Life and Patient-Reported Outcomes Following Proton Radiation Therapy: A Systematic Review

Quality of Life and Patient-Reported Outcomes Following Proton Radiation Therapy: A Systematic... Abstract Background As costs of cancer care rise, the importance of documenting value in oncology increases. Proton beam radiotherapy (PBT) has the potential to reduce toxicities in cancer patients, but is relatively expensive and unproven. Evaluating quality of life (QOL) and patient-reported outcomes (PROs) is essential to establishing PBT’s “value” in oncologic therapy. The goal of this systematic review was to assess QOL and PROs in patients treated with PBT. Methods Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)–guided systematic searches were conducted. The PubMed search engine was the primary data source, along with publications found from references of selected articles, and articles known to the authors published through 2017. Seventeen original investigations were found to have sufficient focus and relevance to be incorporated into the systematic review. Results Studies of skull base (n = 1), brain (n = 1), head/neck (n = 1), lung (n = 1), breast (n = 2), prostate (n = 8), and pediatric (n = 3) malignancies treated with PBT that met eligibility criteria were included. QOL did not deteriorate during PBT for skull base and after PBT for brain tumors, respectively. PROs were higher for PBT than photon-based radiotherapy for both head/neck and lung cancer. Patient-reported breast cosmesis was appropriate after PBT and comparable to photon modalities. PBT in various settings of prostate cancer displayed an expected post-therapy decline; one study showed improved PROs (rectal urgency, bowel frequency) for PBT, and two others showed PROs/QOL comparable with other modalities. Pediatric studies demonstrated improvements in QOL during therapy, with additional increases thereafter. Conclusions Based on limited data, PBT provides favorable QOL/PRO profiles for select brain, head/neck, lung, and pediatric cancers; measures for prostate and breast cancers were more modest. These results have implications for cost-effective cancer care and prudently designed QOL evaluation in ongoing trials, which are discussed. Future data could substantially change the conclusions of this review. Cost-effectiveness (CE) and value-based medicine have rapidly emerged as public health priorities. This is, in part, because rising annual costs for cancer care in the United States are expected to reach $173 billion by 2020 (1), coupled with concerns regarding patient financial burden. The goal of value-based oncology (VBO) is to balance clinically relevant outcomes with the monetary costs required to achieve those outcomes. However, a major challenge with VBO relates to defining what constitutes a “clinically relevant outcome” (2). A growing emphasis has now been placed on quality of life (QOL) as a clinically relevant patient-centered outcome. Health-related quality is increasingly utilized in patient and physician shared decision-making (2,3). Likewise, payers and policy makers are tasked with evaluating new treatment approaches not only in terms of any incremental improvements in survival and toxicity rates, but also in terms of overall costs. Although most CE analyses focus on direct healthcare costs, long-term QOL declines can lead to a substantial increase in indirect costs that are due to treatment morbidity (4). As a result, it is becoming essential to carefully analyze subjective measures such as QOL when evaluating the comparative effectiveness of new treatment approaches. QOL is an inherently multidimensional concept that is dependent on various perspectives, and without a unified definition (5,6). Several validated QOL and PRO questionnaires are used in oncologic clinical research. QOL measures, such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) and the Pediatric QOL Questionnaire (PedsQoL), evaluate functional, symptomatic, and psychosocial elements of cancer therapy, along with more disease-focused measures and a composite global parameter. PROs, which are more tailored toward symptoms, can be general and/or entirely disease specific, such as the MD Anderson Symptom Inventory (MDASI), Harvard Breast Cosmesis Scale, Expanded Prostate Cancer Index Composite (EPIC), and Prostate Cancer Symptom Index (PCSI). Both types of questionnaires are usually administered before therapy and at various subsequent intervals during or after treatment. QOL and PROs are especially relevant to oncology given the unprecedented proliferation of surgical innovations, biologic therapies, and radiation therapy (RT) technologies. A prime example of these radiation technologies is proton beam therapy (PBT), which has grown exponentially worldwide over the present decade and is likely to continue at an even greater pace in the near future (7). The dosimetric advantages of PBT over intensity-modulated RT (IMRT) and 3D-conformal RT (3DCRT) have been buoyed by emerging clinical data demonstrating PBT to be a safe and effective option to treat many neoplasms (8–22). The promise of PBT has been primarily attributed to potential toxicity reductions and attenuation of post-treatment QOL decline. However, proton facilities are expensive and do not yet have mature phase III data to support routine utilization (23). The result has been a sometimes intense debate about the use of PBT in a VBO system (24). A major challenge in analyzing the CE of PBT is the lack of comprehensive evaluations of QOL/PRO results for PBT. Indeed, the majority of economic studies, which use the primary measure of cost per quality-adjusted life-year, do not actually account for QOL (25). In addition, critical assessment of existing QOL data is a main prerequisite for well-designed evaluation of QOL in ongoing trials. This systematic review focusing on QOL and PROs in patients treated with PBT is intended to address this need. We critically appraise available QOL/PRO evidence, relate the findings to CE and VBO, and identify current knowledge gaps. Methods This systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (26). Eligibility criteria included published work in English evaluating QOL and/or PROs during and/or following proton RT. The PubMed search engine was the primary data source, along with publications found from references of selected articles and articles known to the authors. Unpublished abstracts were not included because of the inability to completely assess validity and methodologies. Searches were intended to identify all articles addressing this subject with the following search terms: proton, proton therapy, proton radiation therapy, proton beam therapy, quality of life, QOL, and patient-reported outcomes. Care was taken to ensure that the inclusion criteria were sufficiently broad so that possibly pertinent publications could be assessed by individual screening rather than being excluded by the initial search. Systematic searches, conducted by all authors, did not utilize date restrictions and included articles published through March 2017. It was not possible to perform a meta-analysis on the available literature because of the inherent heterogeneity in study designs, scale, and characteristics. Based on the initial searches, a total of 223 articles were identified (Figure 1). Several journal publications were from the same group of researchers and analyzed overlapping patient populations. In such instances, the prioritized publication had a higher sample size, was more recent, and/or performed a broader spectrum of QOL/PRO analyses. An exception was made for two studies evaluating QOL/PROs while stratifying for a salient clinical variable (eg, history of a procedure that could impact QOL/PROs) that had been unreported in a prior analysis. After duplicates were removed, each of the 216 remaining eligible items was independently screened for the inclusion criteria, and a further 193 were determined to be ineligible. Articles were excluded for several reasons, including but not limited to transient references to QOL/PROs without specific analyses, nonoriginal research (eg, letters to the editor, commentary, or review articles), and QOL/PRO studies of other RT modalities with references to PBT. Of the 23 publications remaining, six were further eliminated because they lacked quantitative assessment, measured other non-QOL end points (eg, clinician-scored toxicities) from a QOL database, or evaluated objective measures alone (ie, without a prominent subjective component, such as intelligence quotient [IQ] only). Thus, 17 original investigations were found to have sufficient focus and relevance to be incorporated into the systematic review. Figure 1. View largeDownload slide PRISMA diagram illustrating systematic searches incorporated into this review. Figure 1. View largeDownload slide PRISMA diagram illustrating systematic searches incorporated into this review. Results Skull Base, Brain, Head and and Neck, and Thorax Table 1 provides details of the studies included in this review. Srivastava et al. conducted a small (n = 17) retrospective study of chordomas and chondrosarcomas using the EORTC-QLQ to evaluate QOL before and after treatment (27). Although no end point past the immediate post-treatment period was evaluated, mean pre- and post-PBT scores were not statistically different, suggesting that QOL was not adversely affected by PBT. Although this and several studies to be discussed did not compare photon and PBT treatment, measuring of QOL/PRO trends over time in a single arm can serve as a starting point to facilitate more rigorous future comparisons. Table 1. Details regarding quality-of-life studies of head, neck, and thoracic neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  * 3DCRT = 3D conformal radiation therapy; BVMT = Brief Visual Memory Test; EORTC = European Organization for the Research and Treatment of Cancer; FACT = Functional Assessment of Cancer Therapy (brain); Gy RBE = Gray relative biological effectiveness; H&N = head and neck; HVLT = Hopkins Verbal Learning Test; IMPT = intensity-modulated proton therapy; IMRT = intensity-modulated radiation therapy; MDASI = MD Anderson Symptom Inventory; PS = performance status; QOL = quality of life; PBT = proton beam therapy; PROs = patient-reported outcomes; QLQ = quality of life questionnaire; RT = radiotherapy; WAIS = Wechsler Adult Intelligence Scale. Table 1. Details regarding quality-of-life studies of head, neck, and thoracic neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  * 3DCRT = 3D conformal radiation therapy; BVMT = Brief Visual Memory Test; EORTC = European Organization for the Research and Treatment of Cancer; FACT = Functional Assessment of Cancer Therapy (brain); Gy RBE = Gray relative biological effectiveness; H&N = head and neck; HVLT = Hopkins Verbal Learning Test; IMPT = intensity-modulated proton therapy; IMRT = intensity-modulated radiation therapy; MDASI = MD Anderson Symptom Inventory; PS = performance status; QOL = quality of life; PBT = proton beam therapy; PROs = patient-reported outcomes; QLQ = quality of life questionnaire; RT = radiotherapy; WAIS = Wechsler Adult Intelligence Scale. A prospective study of 20 patients with low-grade gliomas (LGGs) treated with PBT was notable for assessing a diverse array of QOL measures (28). With a median follow-up of 5.1 years, no declines were noted in executive function, processing speed, verbal/visual/working memory, or visuospatial and intelligence domains. Statistical improvements (per year) were seen in QOL scores for fatigue and visuospatial parameters. This study had notable limitations, including a relatively small and heterogeneous cohort comprising both primary (n = 8) and recurrent (n = 12) LGGs, as well as patients with prior symptomatology leading to PBT initiation. QOL for patients who progressed was not reported. Investigators at MD Anderson Cancer Center reported a prospective QOL registry-based comparison of oropharyngeal cancer treated with definitive chemoradiation using intensity-modulated proton therapy (IMPT; n = 35) or IMRT (n = 46) (29). The authors used the head and neck MDASI instrument and grouped PROs by time course (during RT, acute; three or fewer months from RT, subacute; more than three months from RT, chronic). IMPT was associated with improved PROs compared to IMRT, most notably in the subacute period (taste, appetite), and resulted in a lower proportion of patients with moderate-to-severe taste and mucus impairments. IMPT also improved overall PRO scores when collectively assessing the five most frequent symptoms (which varied between measurement periods). Along with the relatively short (median = 7.7 months) follow-up, the data were confounded by the higher baseline QOL and lower doses delivered in the IMPT group. The study did not report stratification for performance status, smoking history, socioeconomic status, or p16 status. A report from the same institution evaluated 82 locally advanced non–small cell lung cancer (NSCLC) patients treated with definitive chemoradiation using PBT (n = 26), IMRT (n = 34), or 3DCRT (n = 22) (30). The lung MDASI was utilized. All three groups displayed PRO declines during treatment; these persisted up to five weeks post-therapy in the photon cohort but not the PBT cohort. PBT was also associated with better scores in treatment-related pain and drowsiness. The multivariable analysis showed PBT to be independently associated with post-RT systemic symptoms, including pain. It is also noteworthy that patients in the PBT group receiving the highest RT doses (median = 71 Gy relative biological effectiveness [GyRBE]) also had higher performance statuses. Differentiating based on tumor bulk and location (eg, central vs more peripheral) was also not addressed. Breast Breast cancer cosmesis is a PRO that is often graded using the Harvard four-point scale (excellent, good, fair, poor) (Table 2). Although clinical data on PBT for breast cancer are limited, two original studies of accelerated partial breast irradiation (APBI) met the inclusion criteria. The only comparative data were part of a phase I trial of PBT (n = 19) and photon-based (n = 79) APBI (31). At median follow-up of 82.5 months, PBT displayed similar excellent late (seven-year) patient-reported cosmetic outcomes (P = .95), although physician-reported cosmesis was statistically significantly worse for PBT patients (P = .03). A unique feature of this study was the use of a patient satisfaction rating, which also displayed no statistical differences between groups at one, five, and seven years post-treatment. A notable limitation to this study was the utilization of only one PBT field treated per day and passively scattered PBT. No data were provided on skin doses received by each group. Table 2. Details regarding patient-reported cosmetic outcomes of partial breast irradiation using proton beam therapy* Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  * CTV = clinical target volume; PTV = planning target volume; Gy RBE = Gray relative biological effectiveness; PROs = patient-reported outcomes; PBT = proton beam therapy; QOL = quality of life. Table 2. Details regarding patient-reported cosmetic outcomes of partial breast irradiation using proton beam therapy* Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  * CTV = clinical target volume; PTV = planning target volume; Gy RBE = Gray relative biological effectiveness; PROs = patient-reported outcomes; PBT = proton beam therapy; QOL = quality of life. Investigators at Loma Linda University performed a noncomparative prospective investigation of 100 breast cancer patients treated with PBT (32). This differed from the previous report (31) in terms of dose (40 GyRBE delivered in 10 daily fractions, vs 32 GyRBE twice daily) (31), treatment of multiple fields per fraction, and prone setup with smaller total margins. At median follow-up of 60 months, the authors concluded that PBT resulted in appropriate cosmesis, with excellent or good results in at least 90% of patients at each measured time point (one, three, and five years). Prostate Complete details of the prostate cancer studies in this analysis are included in Table 3. Talcott et al. performed a cross-sectional analysis of 280 patients in the Proton Radiation Oncology Group 9509 trial, evaluating 19.8 vs 20.8 GyRBE of PBT boost treatment after 50.4 Gy photon therapy (33). The PCSI scale was the primary PRO utilized, and the median follow-up was 9.4 years. The primary findings of no differences between arms (with lower cancer control concerns and regret in the high-dose cohort) led to a conclusion of no association between dose escalation and worse PROs. In addition to the shortcomings of a cross-sectional analysis using combined photon/PBT treatment, baseline symptoms were not assessed for comparison, which was a major confounding factor. Table 3. Details regarding quality-of-life studies of prostate cancer treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  * ADT = androgen deprivation therapy; CIRT = carbon ion radiation therapy; CS = cryosurgery; EORTC = European Organization for the Research and Treatment of Cancer; EPIC = Expanded Prostate Cancer Index Composite; Gy RBE = Gray relative biological effectiveness; HIFU = high-intensity focused ultrasound; IPSS = International Prostate Symptom Score; O/I = obstruction/irritation; PBT = proton beam therapy; PCSI = prostate cancer symptom index; PROG = Proton Radiation Oncology Group; PROs = patient-reported outcomes; QLQ = Quality of Life Questionnaire; QOL = quality of life; RBE = relative biological effectiveness; RT = radiation therapy; TURP = transurethral resection of the prostate. Table 3. Details regarding quality-of-life studies of prostate cancer treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  * ADT = androgen deprivation therapy; CIRT = carbon ion radiation therapy; CS = cryosurgery; EORTC = European Organization for the Research and Treatment of Cancer; EPIC = Expanded Prostate Cancer Index Composite; Gy RBE = Gray relative biological effectiveness; HIFU = high-intensity focused ultrasound; IPSS = International Prostate Symptom Score; O/I = obstruction/irritation; PBT = proton beam therapy; PCSI = prostate cancer symptom index; PROG = Proton Radiation Oncology Group; PROs = patient-reported outcomes; QLQ = Quality of Life Questionnaire; QOL = quality of life; RBE = relative biological effectiveness; RT = radiation therapy; TURP = transurethral resection of the prostate. Gray et al. presented a pooled experience of prospectively collected PROs (using both EPIC and PCSI) in 371 patients treated with PBT (n = 95), IMRT (n = 153), or 3DCRT (n = 123) (34). Dosing in this study was heterogeneous and depended on the specific institution and treatment era; the final endpoint was relatively short at 24 months. At two to three months, all groups experienced decline in urinary obstruction/irritation scores. Bowel scores statistically significantly declined in both photon groups, whereas they only trended toward decline in the PBT group (P = .06). Patients receiving IMRT reported statistically worse incontinence than those receiving PBT or 3DCRT. At 12 and 24 months, all groups had notable bowel PRO decline, with no clear differentiation between PROs in the PBT and photon groups. The authors concluded that PBT resulted in PRO declines similar to those with photon-based modalities. A publication from the University of Florida prospectively collected PRO information on 1447 patients (n = 1243 PBT, n = 204 IMRT) (35). The PBT patients were younger, less likely to receive androgen deprivation therapy, had smaller prostate sizes, and had higher baseline PRO scores. No patient received pelvic nodal RT. In patients not receiving androgen deprivation therapy, EPIC score reductions were similar between groups (last time period, 24 months), with the PBT cohort reporting statistically improved scores for rectal urgency (P = .02) and bowel frequency (P = .05). Pugh et al. performed a prospective analysis of 423 low- to intermediate-risk patients treated with PBT (36). The EPIC instrument was used, although at nonstandardized intervals. The main result of this noncomparative observational study was a clinically significant (generally defined as ≥ 50% of the standard deviation) decline in urinary and bowel subscale scores; whereas urinary function/bother and obstruction/irritation statistically normalized by six months, incontinence and bowel PRO declines persisted. However, there was no stratification for ADT as well as nonuniform duration of use. A study from the Proton Collaborative Group prospectively treated 49 low-risk patients with hypofractionated PBT (38 GyRBE in five fractions) (37). The group observed decreased urinary, bowel, and sexual EPIC scores at the latest time point of 24 months, along with worsened American Urological Association scores at 12 and 18 months. This represents the only eligible study on PBT-based stereotactic radiation therapy, but the results should not be generalized to the nonhypofractionated setting. A phase II comparison of PBT with carbon ion RT (n = 46 each) from the Heidelberg Ion Therapy Center evaluated a more modestly hypofractionated approach (66 GyRBE in 20 fractions) and was the only prostate PBT study to assess QOL (EORTC-QLQ), although at a shortened follow-up of up to six months post-treatment (38). This study is also unique for the placement of a gel spacer prior to RT. The report detailed QOL parameters that initially declined but improved at six weeks and six months (this analysis did not compare by modality). Overall, the urinary and bowel QOL was higher in the carbon ion RT arm, although the authors concluded that QOL was comparable in both groups. Two additional studies from the University of Florida experience were included because of assessment and stratification by prior transurethral resection of the prostate (TURP) and cryosurgery/high-intensity focused ultrasound (CS/HIFU) (39,40). In one study, 1289 patients were stratified into those with prior TURP (n = 96) and those without (n = 1193). This investigation (median follow-up = 5.3 years) was important because it established that TURP was associated with worse initial PROs. However, differences in obstructive and bowel PROs remitted by one and two years, respectively. Incontinence and sexual PROs remained low at the three-year time period. Additionally, the TURP group was older, at higher risk (unknown receipt of pelvic nodal RT), and had greater ADT and 5α-reductase inhibitor usage. The second report described 21 patients treated with PBT following local recurrence after initial CS/HIFU. Based on scores at 12 months, all parameters were stable in the shorter term, except bowel scores, which were clinically lower. Pediatric Table 4 summarizes the three eligible analyses of pediatric neoplasms. A notable prospective study by Kuhlthau et al. of 142 different pediatric brain tumors (and thus heterogeneous treatment volumes) was designed to evaluate clinical factors associated with QOL (41). The group used a diverse battery of QOL and neurobehavioral tests. QOL rose from the start to the end of PBT (in both craniospinal irradiation [CSI] and non-CSI patients), and less so thereafter to three years. Clinical factors associated with poorer QOL included baseline scores, posterior fossa location, receipt of CSI, and histology of germ cell or primitive neuroectodermal tumor. Associated treatment factors were receipt of chemotherapy and therapy with either PBT alone or trimodality therapy. Although factors associated with worse QOL at later end points were not explicitly assessed, the study provided a valuable framework for further inquiry. Table 4. Details regarding quality of life studies of pediatric neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  * BASC = Behavior Assessment System for Children; ATRT = atypical teratoid rhabdoid tumor; CSI = craniospinal irradiation; Gy RBE = Gray relative biological effectiveness; IQ = intelligence quotient; LGG = low-grade glioma; PNET = primitive neuroectodermal tumor; PROs = patient-reported outcomes; QOL = quality of life; PedQoL = pediatric quality of life; SIB-R = Scale of Independent Behavior, Revised. Table 4. Details regarding quality of life studies of pediatric neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  * BASC = Behavior Assessment System for Children; ATRT = atypical teratoid rhabdoid tumor; CSI = craniospinal irradiation; Gy RBE = Gray relative biological effectiveness; IQ = intelligence quotient; LGG = low-grade glioma; PNET = primitive neuroectodermal tumor; PROs = patient-reported outcomes; QOL = quality of life; PedQoL = pediatric quality of life; SIB-R = Scale of Independent Behavior, Revised. Two retrospective series from the Paul Scherrer Institute (using pencil-beam scanning PBT) were assessed. The first evaluated PedsQOL results in 15 patients with atypical teratoid/rhabdoid tumor with a median 33-month follow-up (42). The results were similar to those of Kuhlthau and colleagues (41), chiefly that most QOL scores tended to increase as treatment progressed. This was also reflected in another study of rhabdomyosarcoma (43), which included 93 patients, 34 of whom completed the questionnaire (patients younger than age five years were excluded). The scores were matched with those from a proxy “normal” population. The findings supported prior data: QOL improved in all domains starting at the two-month mark and continued to improve throughout the first year after therapy. The authors noted that at the two-year time point, most QOL domains were comparable to or higher than those in the proxy normal population. Discussion The major factors driving implementation and critical evaluation of PBT include relative potential toxicity reductions and improvements in post-treatment QOL decline. To that extent, this is the first systematic review comprehensively and critically reviewing QOL and PRO outcomes following PBT. These findings have notable implications for stakeholders, VBO, and PBT clinical trial design. The available evidence suggests that PBT provides favorable QOL/PRO profiles for select brain, head/neck, lung, and pediatric cancers. A complete discussion of analogous photon studies is beyond the scope of this paper, and substantial heterogeneity characterizes QOL/PRO studies. However, select data from this review will be briefly discussed. As compared with the findings by Shih et al. (28), QOL assessment of a phase III LGG trial of photon RT (without chemotherapy) displayed steady declines in both QOL and mental state questionnaire results (44). Regarding head/neck cancers, for which QOL studies are especially subject to bias from patient and treatment parameters, there were notable QOL declines with more aggressive therapy, which also associated with a greater symptom burden (45). To this extent, the finding of generally lower toxicities for PBT than for photon therapy could be noteworthy and supports the aforementioned (and other) data from MD Anderson indicating lower rates of feeding tube requirements with IMPT (46,47). In locally advanced NSCLC, the results from Wang et al. (30) are consistent in the context of QOL data from a recent phase III dose escalation study showing notable QOL declines in both arms (more so in the high-dose arm) (48). Perhaps most notably, the fact that higher conformality of IMRT was associated with fewer functional assessment score declines than 3DCRT could suggest favorable results for IMPT in subsequent comparisons with IMRT. For pediatric malignancies, QOL results were relatively corroborative, with all three reports suggesting QOL improvements (and not declines) during and after PBT. Although the gradual relief of initial anxiety plays a clear role in these results (highlighting the importance of actively involving child life specialists and/or psychologists), they should also be considered in the context of photon data demonstrating decreases in QOL steadily after RT (49,50). In addition, a retrospective comparison (51) of post-therapy IQ in PBT and photon RT has demonstrated greater decline with photon RT, although the rate of decline was not different between groups. Post-PBT QOL/PRO results for breast and prostate cancers were more modest. There was only one comparative study in breast cancer showing no differences between PBT and photons, which is consistent with prospective data reporting comparable pre- and post-RT QOL with photon RT (52). However, the fact that PBT can be utilized in the APBI setting is important because a recent secondary analysis of phase III data indicated that photon APBI results in higher QOL than conventionally fractionated photon whole-breast RT (53). Prostate cancer is currently the focus of the greatest amount of QOL/PRO data; results for PBT analyzed here in are consistent with findings of retrospectively (54,55) and prospectively collected (56) data displaying no differences in toxicities between PBT and IMRT. However, the finding that stereotactic RT (acknowledging the impact of various dosing regimens) does not produce worse QOL than moderate hypofractionation could be implemented to alter QOL outcomes in future analyses (57). The main conclusions of this review roughly mirror those of the CE of PBT (25) and further illustrate the connection—and, to some extent, interdependence—between QOL and CE. It has been proposed that, based on limited evidence, PBT is cost-effective for pediatric brain neoplasms, locally advanced NSCLC, and some head and neck cancers; it was not cost-effective for prostate cancer and unselected breast cancer cases. Indeed, although these and future QOL/PRO findings will substantially impact the results of future CE analyses, these investigations must utilize QOL data much more frequently than at present (25). More important is the identification of the best methods to integrate QOL into CE studies by relating QOL data to utility values and numeric relationships with cost. This will undoubtedly require major extrapolation (clearly already the basis for CE studies), but the real importance of further data will be when averaging the values from multiple QOL studies instead of complete reliance on single investigations (thus decreasing bias). In addition, QOL (and CE) data are urgently needed for neoplasms for which PBT could offer intuitive advantages (eg, postoperative toxicity/complication reduction in esophageal cancer) (16). One major impact of these and other QOL data on health policy and VBO can be seen in statements made by the American Society of Clinical Oncology (ASCO) Value in Cancer Care Task Force (58). This group initially constructed a quantitative “net health benefit” score associated with a particular intervention, referring to balancing its potential “clinical benefits” with costs. When performing revisions to the initial framework, the Task Force noted a prominent deficiency in both PRO and QOL information. However, the presence of available supportive QOL/PRO information now results in “bonus points” assigned to the net health benefit score. This has been a major step in directly integrating QOL/PRO data with the quantitative metrics of CE. The findings of this systematic review will likely be of interest not only to the Task Force and ASCO’s Quality Oncology Practice Initiative (59) but also to stakeholders using similar metrics to assess the “net health benefits” of PBT. These findings also have implications for ongoing clinical trials (60). As evidence of the increased focus of QOL in these investigations, Table 5 displays currently accruing prospective trials of PBT (registered on clinicaltrials.gov as of March 2017) that have specifically listed QOL as an endpoint. This includes five phase III trials; three studies list QOL/PRO as the primary endpoint. The primary endpoints of most trials are toxicity related, which highlights the need to actively associate these toxicity endpoints with QOL endpoints. Doing so will not only enhance the importance of potential toxicity reductions afforded by PBT for QOL but also serve to more directly integrate QOL metrics into future CE studies. We also encourage clinical trials to include high-quality, validated PRO/QOL assessments prospectively in the most homogeneous populations possible. Emphasis should be placed on global health-related QOL, which provides a unique and important parameter that could be most indicative of PBT efficacy (analogous to the primacy of overall survival as a primary endpoint in many trials). Trials should aim to identify as many sources of potential QOL/PRO bias as possible when performing initial data collection. Many of the studies discussed in this review did not stratify for socioeconomic, marital, employment, or comorbidity status. Organ-specific parameters are equally important, as these will have a major impact on QOL, and consideration should be given to factors like smoking history, prostate volume (only two analyzed studies reported this), prior surgeries, and relevant medications (per Lee et al. [35]). Disease-specific factors are also needed, including but not limited to genomic/molecular data, tumor location (eg, at a high-risk anatomic area), and disease volume. Finally, the majority of studies did not conduct multivariable adjustment of QOL based on treatment modality, and this should also be performed whenever possible. Table 5. Accruing prospective trials of proton therapy, registered on Clinicaltrials.gov as of March 2017, that have specifically listed quality of life as an end point* Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  * CNS = central nervous system; FFF = freedom from failure; IBTR = ipsilateral breast tumor recurrence; LC = local control; MDACC = MD Anderson Cancer Center; MGH = Massachusetts General Hospital; NSCLC = non-small cell lung cancer; Obs = observational; OS = overall survival; PCG = Proton Collaborative Group; PFS = progression-free survival; QOL = quality of life; RTOG = Radiation Therapy Oncology Group; SMC = Samsung Medical Center; TTB = total tumor burden; TUD = Technische Universität Dresden; WHO = World Health Organization. Table 5. Accruing prospective trials of proton therapy, registered on Clinicaltrials.gov as of March 2017, that have specifically listed quality of life as an end point* Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  * CNS = central nervous system; FFF = freedom from failure; IBTR = ipsilateral breast tumor recurrence; LC = local control; MDACC = MD Anderson Cancer Center; MGH = Massachusetts General Hospital; NSCLC = non-small cell lung cancer; Obs = observational; OS = overall survival; PCG = Proton Collaborative Group; PFS = progression-free survival; QOL = quality of life; RTOG = Radiation Therapy Oncology Group; SMC = Samsung Medical Center; TTB = total tumor burden; TUD = Technische Universität Dresden; WHO = World Health Organization. Lastly, recent advances in PBT delivery techniques, such as at the advent of IMPT and volumetric image guidance, could substantially impact the results of future QOL analyses. For instance, it is important to note that comparison of forward-planned passively scattered PBT (which comprised the dominant technique in the studies discussed herein) is most analogous to photon 3D-CRT. IMRT would more appropriately be compared with inverse-planned IMPT (which, owing to its newer implementation in clinical practice, has much more limited QOL/PRO data available to date. Therefore, existing literature comparing advanced photon techniques with first-generation proton techniques might be inherently biased against proton therapy. There are also biases regarding the learning curve of new technologies such as PBT as compared to more established photon techniques such as IMRT. Additionally, in nonrandomized trials, there are unavoidable selection biases regarding the use of protons vs photons to treat a given patient, such as proximity to organs at risk or ease/difficulty in meeting dose constraints with protons vs photons. Furthermore, in both randomized and nonrandomized trials, insurance status (eg, Medicare is more likely to pay for elderly patients’ PBT, vs other commercial insurances less likely to pay in the non-Medicare population) may play a factor in who receives which type of radiotherapy modality, and this may also have served to bias existing studies reporting on QOL/PROs. Limitations of this work, similar to CE analyses, are that there are no “perfectly conducted” QOL/PRO studies. These parameters are inherently subjective and are influenced by numerous factors, including inherent psychosocial, behavioral, and cultural attitudes. It is impossible for investigations to account for all of these variables, acknowledging that confounding factors will always be present (at the very least, potentially biased in PBT patient selection regarding those with the means to travel longer distances to PBT facilities) (Tables 1–4). Rather, also similar to CE work, the goal of a QOL/PRO investigation is to provide a rough comparison between groups (or observation of a cohort) so that, ideally, further work can be corroborated by additional research. QOL/PRO data are thus important to recognize as constituting a dynamically changing entity that can be substantially influenced by the quality and volume of further additional data (including patient selection) as they are published. Herein, although the overall quality and quantity of data available on QOL and PBT remain relatively low, thus permitting few robust conclusions, there are salient “lessons to be learned” that can allow for sharper and more insightful interpretation of QOL/PRO analyses of active and planned clinical trials. Taken together, the lessons for ongoing clinical trials involve performing high-quality, thorough QOL/PRO evaluations. Doing so may allow for delineation of patient subpopulations that proportionally receive greater QOL (and CE) benefits (as QOL is not a binary term); moreover, it will increase the applicability, impact, validity, and reliability of the data on both future CE analyses and VBO as a whole. This is critical to consider, especially in an ever-changing medico-economic climate. Notes There were no sponsors or funders for this study. All authors declare that conflicts of interest do not exist. References 1 Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. 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Quality of Life and Patient-Reported Outcomes Following Proton Radiation Therapy: A Systematic Review

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© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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0027-8874
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10.1093/jnci/djx208
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Abstract

Abstract Background As costs of cancer care rise, the importance of documenting value in oncology increases. Proton beam radiotherapy (PBT) has the potential to reduce toxicities in cancer patients, but is relatively expensive and unproven. Evaluating quality of life (QOL) and patient-reported outcomes (PROs) is essential to establishing PBT’s “value” in oncologic therapy. The goal of this systematic review was to assess QOL and PROs in patients treated with PBT. Methods Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)–guided systematic searches were conducted. The PubMed search engine was the primary data source, along with publications found from references of selected articles, and articles known to the authors published through 2017. Seventeen original investigations were found to have sufficient focus and relevance to be incorporated into the systematic review. Results Studies of skull base (n = 1), brain (n = 1), head/neck (n = 1), lung (n = 1), breast (n = 2), prostate (n = 8), and pediatric (n = 3) malignancies treated with PBT that met eligibility criteria were included. QOL did not deteriorate during PBT for skull base and after PBT for brain tumors, respectively. PROs were higher for PBT than photon-based radiotherapy for both head/neck and lung cancer. Patient-reported breast cosmesis was appropriate after PBT and comparable to photon modalities. PBT in various settings of prostate cancer displayed an expected post-therapy decline; one study showed improved PROs (rectal urgency, bowel frequency) for PBT, and two others showed PROs/QOL comparable with other modalities. Pediatric studies demonstrated improvements in QOL during therapy, with additional increases thereafter. Conclusions Based on limited data, PBT provides favorable QOL/PRO profiles for select brain, head/neck, lung, and pediatric cancers; measures for prostate and breast cancers were more modest. These results have implications for cost-effective cancer care and prudently designed QOL evaluation in ongoing trials, which are discussed. Future data could substantially change the conclusions of this review. Cost-effectiveness (CE) and value-based medicine have rapidly emerged as public health priorities. This is, in part, because rising annual costs for cancer care in the United States are expected to reach $173 billion by 2020 (1), coupled with concerns regarding patient financial burden. The goal of value-based oncology (VBO) is to balance clinically relevant outcomes with the monetary costs required to achieve those outcomes. However, a major challenge with VBO relates to defining what constitutes a “clinically relevant outcome” (2). A growing emphasis has now been placed on quality of life (QOL) as a clinically relevant patient-centered outcome. Health-related quality is increasingly utilized in patient and physician shared decision-making (2,3). Likewise, payers and policy makers are tasked with evaluating new treatment approaches not only in terms of any incremental improvements in survival and toxicity rates, but also in terms of overall costs. Although most CE analyses focus on direct healthcare costs, long-term QOL declines can lead to a substantial increase in indirect costs that are due to treatment morbidity (4). As a result, it is becoming essential to carefully analyze subjective measures such as QOL when evaluating the comparative effectiveness of new treatment approaches. QOL is an inherently multidimensional concept that is dependent on various perspectives, and without a unified definition (5,6). Several validated QOL and PRO questionnaires are used in oncologic clinical research. QOL measures, such as the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ) and the Pediatric QOL Questionnaire (PedsQoL), evaluate functional, symptomatic, and psychosocial elements of cancer therapy, along with more disease-focused measures and a composite global parameter. PROs, which are more tailored toward symptoms, can be general and/or entirely disease specific, such as the MD Anderson Symptom Inventory (MDASI), Harvard Breast Cosmesis Scale, Expanded Prostate Cancer Index Composite (EPIC), and Prostate Cancer Symptom Index (PCSI). Both types of questionnaires are usually administered before therapy and at various subsequent intervals during or after treatment. QOL and PROs are especially relevant to oncology given the unprecedented proliferation of surgical innovations, biologic therapies, and radiation therapy (RT) technologies. A prime example of these radiation technologies is proton beam therapy (PBT), which has grown exponentially worldwide over the present decade and is likely to continue at an even greater pace in the near future (7). The dosimetric advantages of PBT over intensity-modulated RT (IMRT) and 3D-conformal RT (3DCRT) have been buoyed by emerging clinical data demonstrating PBT to be a safe and effective option to treat many neoplasms (8–22). The promise of PBT has been primarily attributed to potential toxicity reductions and attenuation of post-treatment QOL decline. However, proton facilities are expensive and do not yet have mature phase III data to support routine utilization (23). The result has been a sometimes intense debate about the use of PBT in a VBO system (24). A major challenge in analyzing the CE of PBT is the lack of comprehensive evaluations of QOL/PRO results for PBT. Indeed, the majority of economic studies, which use the primary measure of cost per quality-adjusted life-year, do not actually account for QOL (25). In addition, critical assessment of existing QOL data is a main prerequisite for well-designed evaluation of QOL in ongoing trials. This systematic review focusing on QOL and PROs in patients treated with PBT is intended to address this need. We critically appraise available QOL/PRO evidence, relate the findings to CE and VBO, and identify current knowledge gaps. Methods This systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (26). Eligibility criteria included published work in English evaluating QOL and/or PROs during and/or following proton RT. The PubMed search engine was the primary data source, along with publications found from references of selected articles and articles known to the authors. Unpublished abstracts were not included because of the inability to completely assess validity and methodologies. Searches were intended to identify all articles addressing this subject with the following search terms: proton, proton therapy, proton radiation therapy, proton beam therapy, quality of life, QOL, and patient-reported outcomes. Care was taken to ensure that the inclusion criteria were sufficiently broad so that possibly pertinent publications could be assessed by individual screening rather than being excluded by the initial search. Systematic searches, conducted by all authors, did not utilize date restrictions and included articles published through March 2017. It was not possible to perform a meta-analysis on the available literature because of the inherent heterogeneity in study designs, scale, and characteristics. Based on the initial searches, a total of 223 articles were identified (Figure 1). Several journal publications were from the same group of researchers and analyzed overlapping patient populations. In such instances, the prioritized publication had a higher sample size, was more recent, and/or performed a broader spectrum of QOL/PRO analyses. An exception was made for two studies evaluating QOL/PROs while stratifying for a salient clinical variable (eg, history of a procedure that could impact QOL/PROs) that had been unreported in a prior analysis. After duplicates were removed, each of the 216 remaining eligible items was independently screened for the inclusion criteria, and a further 193 were determined to be ineligible. Articles were excluded for several reasons, including but not limited to transient references to QOL/PROs without specific analyses, nonoriginal research (eg, letters to the editor, commentary, or review articles), and QOL/PRO studies of other RT modalities with references to PBT. Of the 23 publications remaining, six were further eliminated because they lacked quantitative assessment, measured other non-QOL end points (eg, clinician-scored toxicities) from a QOL database, or evaluated objective measures alone (ie, without a prominent subjective component, such as intelligence quotient [IQ] only). Thus, 17 original investigations were found to have sufficient focus and relevance to be incorporated into the systematic review. Figure 1. View largeDownload slide PRISMA diagram illustrating systematic searches incorporated into this review. Figure 1. View largeDownload slide PRISMA diagram illustrating systematic searches incorporated into this review. Results Skull Base, Brain, Head and and Neck, and Thorax Table 1 provides details of the studies included in this review. Srivastava et al. conducted a small (n = 17) retrospective study of chordomas and chondrosarcomas using the EORTC-QLQ to evaluate QOL before and after treatment (27). Although no end point past the immediate post-treatment period was evaluated, mean pre- and post-PBT scores were not statistically different, suggesting that QOL was not adversely affected by PBT. Although this and several studies to be discussed did not compare photon and PBT treatment, measuring of QOL/PRO trends over time in a single arm can serve as a starting point to facilitate more rigorous future comparisons. Table 1. Details regarding quality-of-life studies of head, neck, and thoracic neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  * 3DCRT = 3D conformal radiation therapy; BVMT = Brief Visual Memory Test; EORTC = European Organization for the Research and Treatment of Cancer; FACT = Functional Assessment of Cancer Therapy (brain); Gy RBE = Gray relative biological effectiveness; H&N = head and neck; HVLT = Hopkins Verbal Learning Test; IMPT = intensity-modulated proton therapy; IMRT = intensity-modulated radiation therapy; MDASI = MD Anderson Symptom Inventory; PS = performance status; QOL = quality of life; PBT = proton beam therapy; PROs = patient-reported outcomes; QLQ = quality of life questionnaire; RT = radiotherapy; WAIS = Wechsler Adult Intelligence Scale. Table 1. Details regarding quality-of-life studies of head, neck, and thoracic neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Srivastava et al., 2013 (27)  17  Primary postoperative chordoma or chondrosarcoma  70–74  EORTC QLQ C-30: global health status, 5 functional scales, 3 symptoms, 6 single items Measured immediately pre- and post-treatment  Mean pre- vs post-treatment scores in all parameters similar (P > .05) Parameters most likely to clinically worsen: global, fatigue Parameters most likely to be unchanged: cognition, role functioning  QOL does not deteriorate during PBT  Small study with short follow-up Unknown reporting of disease volume Inclusion of paraspinal cases (29%) Reporting of mean QOL scores Unclear when baseline QOL recorded with respect to surgery  Shih et al., 2015 (28)  20  Primary (n = 8) or recurrent (n = 12) LGG, most (n = 16) after surgery  54  Several, including WAIS, HVLT, Beck depression/anxiety test, FACT, Trail Making Test, BVMT Measured at 3, 6, 12, 24, 36, 48, 60 mo after PBT  No change in QOL scores in intellectual, language, attention, memory, processing speed, emotional, total QOL Statistically significant improvement (per y) in scores for visuospatial and fatigue (P < .05) and executive function (P = .05)  QOL does not deteriorate at median 5.1 y after PBT  Does not account for patients who progressed after PBT (removed off study) Unclear accountability and stratification by marital status, employment Inclusion of 6 patients who were treated for persistent/increased symptoms Of 17 patients with history of seizures, 6 were controlled  Sio et al., 2016 (29)  81  Oropharynx cancer treated definitively with chemotherapy and IMPT vs IMRT  67 (IMPT), 69 (IMRT)  MDASI: general symptoms, psychosocial, pain, functioning Measured during RT (acute), ≤3 mo post-RT (subacute), and >3 mo (chronic)  No difference between groups in acute phase Improved PROs in IMPT group with taste and appetite (P < .05) in subacute phase Improved PROs in IMPT group with appetite (P = .04) in chronic phase Average of highest 5 parameters statistically nonsignificant between groups in acute or chronic phases, statistically significantly improved with IMPT (P = .01) Less moderate-severe taste and mucus in IMPT group during subacute phase  PROs for IMPT higher in multiple parameters, especially within 3 mo after RT  Substantial number (46%) of patients received induction chemotherapy IMPT group with lower dose (P = .002) and less baseline swallowing/mastication difficulty (P = .04) p16 status unbalanced, largely unknown in IMRT group Unclear accountability and stratification by marital status, employment, smoking status, PS  Wang et al., 2016 (30)  82  Locally advanced NSCLC treated with definitive CRT using PBT (n = 26), IMRT (n = 34), 3DCRT (n = 22)  71 (PBT), 65 (IMRT), 62 (3DCRT)  MDASI: pain, sore throat, fatigue, drowsiness, appetite, insomnia Measured weekly for 12 weeks from commencing RT  During RT, 3DCRT, and IMRT with statistical declines in all parameters but insomnia; PBT statistically better regarding pain (P = .02) and drowsiness (P = .05) Up to 5 weeks after RT, 3DCRT and IMRT with persistent declines in multiple parameters; PBT without statistical decline in any (P > .05) Using multivariable modeling, PBT independently associated with lower systemic symptoms after RT, along with improvement in pain (P < .05)  Symptomatic PROs during and after higher for PBT treated patients over IMRT and 3DCRT  Inclusion of both primary and recurrent cases (unknown proportions) with statistically differential likelihood of having received prior surgery or chemotherapy PBT group more likely to have patients with higher PS (P = .02) Unclear accountability and stratification by tumor size and especially location Ambiguity in specific factors (and lack thereof) adjusted for in the multivariable model  * 3DCRT = 3D conformal radiation therapy; BVMT = Brief Visual Memory Test; EORTC = European Organization for the Research and Treatment of Cancer; FACT = Functional Assessment of Cancer Therapy (brain); Gy RBE = Gray relative biological effectiveness; H&N = head and neck; HVLT = Hopkins Verbal Learning Test; IMPT = intensity-modulated proton therapy; IMRT = intensity-modulated radiation therapy; MDASI = MD Anderson Symptom Inventory; PS = performance status; QOL = quality of life; PBT = proton beam therapy; PROs = patient-reported outcomes; QLQ = quality of life questionnaire; RT = radiotherapy; WAIS = Wechsler Adult Intelligence Scale. A prospective study of 20 patients with low-grade gliomas (LGGs) treated with PBT was notable for assessing a diverse array of QOL measures (28). With a median follow-up of 5.1 years, no declines were noted in executive function, processing speed, verbal/visual/working memory, or visuospatial and intelligence domains. Statistical improvements (per year) were seen in QOL scores for fatigue and visuospatial parameters. This study had notable limitations, including a relatively small and heterogeneous cohort comprising both primary (n = 8) and recurrent (n = 12) LGGs, as well as patients with prior symptomatology leading to PBT initiation. QOL for patients who progressed was not reported. Investigators at MD Anderson Cancer Center reported a prospective QOL registry-based comparison of oropharyngeal cancer treated with definitive chemoradiation using intensity-modulated proton therapy (IMPT; n = 35) or IMRT (n = 46) (29). The authors used the head and neck MDASI instrument and grouped PROs by time course (during RT, acute; three or fewer months from RT, subacute; more than three months from RT, chronic). IMPT was associated with improved PROs compared to IMRT, most notably in the subacute period (taste, appetite), and resulted in a lower proportion of patients with moderate-to-severe taste and mucus impairments. IMPT also improved overall PRO scores when collectively assessing the five most frequent symptoms (which varied between measurement periods). Along with the relatively short (median = 7.7 months) follow-up, the data were confounded by the higher baseline QOL and lower doses delivered in the IMPT group. The study did not report stratification for performance status, smoking history, socioeconomic status, or p16 status. A report from the same institution evaluated 82 locally advanced non–small cell lung cancer (NSCLC) patients treated with definitive chemoradiation using PBT (n = 26), IMRT (n = 34), or 3DCRT (n = 22) (30). The lung MDASI was utilized. All three groups displayed PRO declines during treatment; these persisted up to five weeks post-therapy in the photon cohort but not the PBT cohort. PBT was also associated with better scores in treatment-related pain and drowsiness. The multivariable analysis showed PBT to be independently associated with post-RT systemic symptoms, including pain. It is also noteworthy that patients in the PBT group receiving the highest RT doses (median = 71 Gy relative biological effectiveness [GyRBE]) also had higher performance statuses. Differentiating based on tumor bulk and location (eg, central vs more peripheral) was also not addressed. Breast Breast cancer cosmesis is a PRO that is often graded using the Harvard four-point scale (excellent, good, fair, poor) (Table 2). Although clinical data on PBT for breast cancer are limited, two original studies of accelerated partial breast irradiation (APBI) met the inclusion criteria. The only comparative data were part of a phase I trial of PBT (n = 19) and photon-based (n = 79) APBI (31). At median follow-up of 82.5 months, PBT displayed similar excellent late (seven-year) patient-reported cosmetic outcomes (P = .95), although physician-reported cosmesis was statistically significantly worse for PBT patients (P = .03). A unique feature of this study was the use of a patient satisfaction rating, which also displayed no statistical differences between groups at one, five, and seven years post-treatment. A notable limitation to this study was the utilization of only one PBT field treated per day and passively scattered PBT. No data were provided on skin doses received by each group. Table 2. Details regarding patient-reported cosmetic outcomes of partial breast irradiation using proton beam therapy* Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  * CTV = clinical target volume; PTV = planning target volume; Gy RBE = Gray relative biological effectiveness; PROs = patient-reported outcomes; PBT = proton beam therapy; QOL = quality of life. Table 2. Details regarding patient-reported cosmetic outcomes of partial breast irradiation using proton beam therapy* Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  Reference  No.  Treatment status  Dose, Gy RBE  QOL/PRO parameters  Cosmetic outcomes  Conclusions  Criticisms and confounders  Galland-Girodet et al., 2014 (31)  98  Treated with PBT (n = 19) vs photons/mixed (n = 79)  32 (BID)  Harvard 4-point cosmetic scoring (scores 0–3); level of satisfaction with therapy  1-y: PBT excellent (56%), good (44%); photons excellent (60%), good (33%), fair (7%) 5-y: PBT excellent (44%), good (44%), fair (12%); photons excellent (60%), good (33%), fair (7%; P = .69) 7-y: PBT excellent (61%), good (31%), fair (8%); photons excellent (59%), good (37%), fair (4%; P = .95) “Totally satisfied” rating: PBT 94%, 88%, 85% at 1, 5, 7 y; photons 98%, 93%, 96% (P = .96)  Appropriate patient-reported cosmesis with PBT at median 82.5 mo follow-up  Unclear discrepancy of patient- vs physician-assessed cosmesis; the latter displayed worse cosmetic outcomes with PBT (P = .03) Nonstandard patient satisfaction measure without information regarding prior validation Skin doses not reported between arms; one PBT field per fraction utilized  Bush et al., 2014 (32)  100  All treated with multifield PBT  40 (QD)  Harvard 4-point cosmetic scoring (scores 0–3)  1-y: excellent or good in 90% 3-y: excellent or good in 95% 5-y: excellent or good in 96%  Appropriate patient-reported cosmesis with PBT at median 60 mo follow-up  Unclear standardization and amount of editing CTV from skin Utilized nonstandard prone positioning Margins from lumpectomy cavity to PTV were 1 cm + 2 mm  * CTV = clinical target volume; PTV = planning target volume; Gy RBE = Gray relative biological effectiveness; PROs = patient-reported outcomes; PBT = proton beam therapy; QOL = quality of life. Investigators at Loma Linda University performed a noncomparative prospective investigation of 100 breast cancer patients treated with PBT (32). This differed from the previous report (31) in terms of dose (40 GyRBE delivered in 10 daily fractions, vs 32 GyRBE twice daily) (31), treatment of multiple fields per fraction, and prone setup with smaller total margins. At median follow-up of 60 months, the authors concluded that PBT resulted in appropriate cosmesis, with excellent or good results in at least 90% of patients at each measured time point (one, three, and five years). Prostate Complete details of the prostate cancer studies in this analysis are included in Table 3. Talcott et al. performed a cross-sectional analysis of 280 patients in the Proton Radiation Oncology Group 9509 trial, evaluating 19.8 vs 20.8 GyRBE of PBT boost treatment after 50.4 Gy photon therapy (33). The PCSI scale was the primary PRO utilized, and the median follow-up was 9.4 years. The primary findings of no differences between arms (with lower cancer control concerns and regret in the high-dose cohort) led to a conclusion of no association between dose escalation and worse PROs. In addition to the shortcomings of a cross-sectional analysis using combined photon/PBT treatment, baseline symptoms were not assessed for comparison, which was a major confounding factor. Table 3. Details regarding quality-of-life studies of prostate cancer treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  * ADT = androgen deprivation therapy; CIRT = carbon ion radiation therapy; CS = cryosurgery; EORTC = European Organization for the Research and Treatment of Cancer; EPIC = Expanded Prostate Cancer Index Composite; Gy RBE = Gray relative biological effectiveness; HIFU = high-intensity focused ultrasound; IPSS = International Prostate Symptom Score; O/I = obstruction/irritation; PBT = proton beam therapy; PCSI = prostate cancer symptom index; PROG = Proton Radiation Oncology Group; PROs = patient-reported outcomes; QLQ = Quality of Life Questionnaire; QOL = quality of life; RBE = relative biological effectiveness; RT = radiation therapy; TURP = transurethral resection of the prostate. Table 3. Details regarding quality-of-life studies of prostate cancer treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Talcott et al., 2010 (33)  280  Patients in PROG 9509 trial (low-intermediate risk without ADT); mixed photon-PBT  50.4 + 19.8 vs 28.8  PCSI (urinary incontinence, O/I, bowel, sexual) and patient attitude scales (cancer/PSA control, informed decision, regret, worry) measured at median 9.4 y post-therapy  No differences between groups in PCSI or level of urinary, bowel, sexual function Overall most bother with sexual function; most bothersome PROs if incontinent Largest components of attitude scores were cancer/PSA control, informed decision Lower regret and cancer control concerns in high-dose arm (P < .05)  At median 9.4 y follow-up, higher-dose therapy not associated with worse symptomatic PROs  Cross-sectional design; as such, analysis limited to survivors that followed up No baseline level of symptoms, or medication use, for comparison Difficult to generalize to patients receiving exclusively PBT and not mixed radiotherapy  Gray et al., 2013 (34)  371  Low-intermediate risk without ADT treated with PBT (n = 95) vs IMRT (n = 153) vs 3DCRT (n = 123)  66.4–82  PCSI and EPIC, measured pretreatment and at 2–3 (acute), 6, 12, and 24 (late) mo thereafter  Acute: IMRT and 3DCRT had bowel PRO decline (P < .05; PBT P = .06); all groups had urinary O/I PRO decline (P < .05); only IMRT had incontinence PRO decline (P < .001) 12 mo: all groups had bowel PRO decline (P < .05); PBT/3DCRT had U/I PRO decline (P < .05); PBT/IMRT had incontinence PRO decline 24 mo: all groups had bowel PRO decline (P < .05); none had U/I PRO decline (P > .05); IMRT had incontinence PRO decline (P = .001)  Overall, PBT with similar urinary and bowel PRO declines as photon modalities  Heterogeneous dosing and treatment planning depending on era and institution Baseline characteristics (eg, race, age) varied between groups, some (eg, prostate volume) not reported Limited sample size at 24-mo end point  Hoppe et al., 2014 (35)  1447  Mostly (88%) low-intermediate risk, 14% ADT treated with PBT (n = 1243) vs IMRT (n = 204)  75.6–79.4 (no pelvic RT)  EPIC (along with hormonal function questions), measured at 6, 12, 24 mo  Statistically insignificant EPIC score declines between groups in non-ADT patients (P > .05) Fewer PBT patients with minimally detectable 6-mo bowel scores from baseline (P = .002) Adjusted comparison of temporal patterns relative to baseline: no differences between groups, except improved rectal urgency (P = .02) and bowel frequency (P = .05) PROs in the PBT group  Comparable PROs in both groups with exception of some bowel parameters  Numerous differences in baseline factors (eg, PBT with smaller prostate size, younger, less ADT) No quantitation of urinary medications Baseline PROs favored PBT group in subparameters in all 4 EPIC categories  Pugh et al., 2016 (36)  423  Low-intermediate risk, 37% ADT  75.6–78, pelvic RT unknown  EPIC measured at 3–6/6–12 mo intervals for 4 y  Clinically significant (≥50% SD) urinary PRO decline at 3 mo; bother/function and O/I statistically normalize by 6 mo, but incontinence remains statistically lower (P < .05) Clinically significant bowel PRO decline starting at 3 mo, persisting thereafter; statistically (not clinically) so for sexual and hormonal PRO as well  PBT associated with modest post-therapy PRO declines, notably bowel  ADT duration nonuniform (median = 6 mo), unclear whether those patients lumped in all QOL analyses Nonstandardized follow-up questionnaire intervals Unclear accountability and stratification by marital status, employment  Vargas et al., 2016 (37)  49  Low risk  38 (5 fractions)  EPIC and AUA pretreatment and at 3, 6, 12, 18, 24 mo thereafter  Decreased urinary scores at 3, 12, 24 mo (P < .05) Decreased bowel scores at all time points (P < .05) Borderline low sexual scores at 18 (P = .06) and 24 (P = .05) mo Worse AUA score at 12 and 18 mo (P < .05)  PROs appropriate for hypofractionated PBT  Difficult to generalize to a more fractionated approach Unclear accountability and stratification by marital status, employment No stratification for symptomatology at diagnosis vs lack thereof  Habl et al., 2016 (38)  92  Low (23%), intermediate (59%), high (17%), PBT (50%) vs CIRT (50%)  66 (20 fractions, no pelvic RT)  EORTC QLQ pre- and post-treatment and at 1.5, 6 mo thereafter  Overall, higher urinary and bowel QOL in CIRT arm (P < .05) By end of RT, elements of the following declined: functioning, fatigue, pain, appetite, bowel, urinary, sexual, global health Recovered by 1.5 mo: global health, social functioning, constipation, sexual Recovered by 6 mo: physical functioning, pain, urinary, bowel Not recovered by 6 mo: role/emotional/cognitive functioning, fatigue, appetite  QOL comparable for PBT and CIRT, potentially higher in CIRT  No statistical comparisons of patient characteristics, no mention of marital status, employment QOL not performed after 6 mo; long-term QOL thus unclear Temporal QOL analysis lumped all patients together  Lee et al., 2016 (39)  1289  Low (42%), intermediate (43%), high (15%), 17% ADT, TURP (7%) vs no TURP (93%)  76–82  EPIC at pre-treatment, 6 mo, and annually thereafter  Baseline bowel, O/I, sexual PROs worse for TURP patients (P < .05) By 1 y, no differences in groups in obstruction PROs (P = .09) By 2 y, no differences in groups in bowel PROs (P = .14) Persistently lower sexual (P = .01) and incontinence (P = .04) QOL in TURP group at 3 y  At median 5.3 y follow-up, lower PRO scores in TURP patients  Imbalanced populations, including TURP group older, higher risk, more ADT, 5α-reductase inhibitors No mention of pelvic RT receipt, marital status, employment Various types and numbers of TURP procedures included; unknown time points relative to PBT  Holtzman et al., 2016 (40)  21  Patients with local recurrence after CS (43%) or HIFU (57%) treated with PBT, 38% ADT, 10% pelvic RT  74–82  EPIC and IPSS measured at baseline, 6 mo, and 12 mo  IPSS, O/I, sexual, incontinence PROs clinically stable from baseline to 6 and 12 mo Bowel PROs clinically worse (≥50% SD) at 12 mo  At median 37 mo follow-up, minimal decline in PROs after salvage PBT  Small study of a specific circumstance limiting generalizability Unclear accountability and stratification by marital status, employment, medications Last PRO scores assessed relatively short term, long term unclear  * ADT = androgen deprivation therapy; CIRT = carbon ion radiation therapy; CS = cryosurgery; EORTC = European Organization for the Research and Treatment of Cancer; EPIC = Expanded Prostate Cancer Index Composite; Gy RBE = Gray relative biological effectiveness; HIFU = high-intensity focused ultrasound; IPSS = International Prostate Symptom Score; O/I = obstruction/irritation; PBT = proton beam therapy; PCSI = prostate cancer symptom index; PROG = Proton Radiation Oncology Group; PROs = patient-reported outcomes; QLQ = Quality of Life Questionnaire; QOL = quality of life; RBE = relative biological effectiveness; RT = radiation therapy; TURP = transurethral resection of the prostate. Gray et al. presented a pooled experience of prospectively collected PROs (using both EPIC and PCSI) in 371 patients treated with PBT (n = 95), IMRT (n = 153), or 3DCRT (n = 123) (34). Dosing in this study was heterogeneous and depended on the specific institution and treatment era; the final endpoint was relatively short at 24 months. At two to three months, all groups experienced decline in urinary obstruction/irritation scores. Bowel scores statistically significantly declined in both photon groups, whereas they only trended toward decline in the PBT group (P = .06). Patients receiving IMRT reported statistically worse incontinence than those receiving PBT or 3DCRT. At 12 and 24 months, all groups had notable bowel PRO decline, with no clear differentiation between PROs in the PBT and photon groups. The authors concluded that PBT resulted in PRO declines similar to those with photon-based modalities. A publication from the University of Florida prospectively collected PRO information on 1447 patients (n = 1243 PBT, n = 204 IMRT) (35). The PBT patients were younger, less likely to receive androgen deprivation therapy, had smaller prostate sizes, and had higher baseline PRO scores. No patient received pelvic nodal RT. In patients not receiving androgen deprivation therapy, EPIC score reductions were similar between groups (last time period, 24 months), with the PBT cohort reporting statistically improved scores for rectal urgency (P = .02) and bowel frequency (P = .05). Pugh et al. performed a prospective analysis of 423 low- to intermediate-risk patients treated with PBT (36). The EPIC instrument was used, although at nonstandardized intervals. The main result of this noncomparative observational study was a clinically significant (generally defined as ≥ 50% of the standard deviation) decline in urinary and bowel subscale scores; whereas urinary function/bother and obstruction/irritation statistically normalized by six months, incontinence and bowel PRO declines persisted. However, there was no stratification for ADT as well as nonuniform duration of use. A study from the Proton Collaborative Group prospectively treated 49 low-risk patients with hypofractionated PBT (38 GyRBE in five fractions) (37). The group observed decreased urinary, bowel, and sexual EPIC scores at the latest time point of 24 months, along with worsened American Urological Association scores at 12 and 18 months. This represents the only eligible study on PBT-based stereotactic radiation therapy, but the results should not be generalized to the nonhypofractionated setting. A phase II comparison of PBT with carbon ion RT (n = 46 each) from the Heidelberg Ion Therapy Center evaluated a more modestly hypofractionated approach (66 GyRBE in 20 fractions) and was the only prostate PBT study to assess QOL (EORTC-QLQ), although at a shortened follow-up of up to six months post-treatment (38). This study is also unique for the placement of a gel spacer prior to RT. The report detailed QOL parameters that initially declined but improved at six weeks and six months (this analysis did not compare by modality). Overall, the urinary and bowel QOL was higher in the carbon ion RT arm, although the authors concluded that QOL was comparable in both groups. Two additional studies from the University of Florida experience were included because of assessment and stratification by prior transurethral resection of the prostate (TURP) and cryosurgery/high-intensity focused ultrasound (CS/HIFU) (39,40). In one study, 1289 patients were stratified into those with prior TURP (n = 96) and those without (n = 1193). This investigation (median follow-up = 5.3 years) was important because it established that TURP was associated with worse initial PROs. However, differences in obstructive and bowel PROs remitted by one and two years, respectively. Incontinence and sexual PROs remained low at the three-year time period. Additionally, the TURP group was older, at higher risk (unknown receipt of pelvic nodal RT), and had greater ADT and 5α-reductase inhibitor usage. The second report described 21 patients treated with PBT following local recurrence after initial CS/HIFU. Based on scores at 12 months, all parameters were stable in the shorter term, except bowel scores, which were clinically lower. Pediatric Table 4 summarizes the three eligible analyses of pediatric neoplasms. A notable prospective study by Kuhlthau et al. of 142 different pediatric brain tumors (and thus heterogeneous treatment volumes) was designed to evaluate clinical factors associated with QOL (41). The group used a diverse battery of QOL and neurobehavioral tests. QOL rose from the start to the end of PBT (in both craniospinal irradiation [CSI] and non-CSI patients), and less so thereafter to three years. Clinical factors associated with poorer QOL included baseline scores, posterior fossa location, receipt of CSI, and histology of germ cell or primitive neuroectodermal tumor. Associated treatment factors were receipt of chemotherapy and therapy with either PBT alone or trimodality therapy. Although factors associated with worse QOL at later end points were not explicitly assessed, the study provided a valuable framework for further inquiry. Table 4. Details regarding quality of life studies of pediatric neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  * BASC = Behavior Assessment System for Children; ATRT = atypical teratoid rhabdoid tumor; CSI = craniospinal irradiation; Gy RBE = Gray relative biological effectiveness; IQ = intelligence quotient; LGG = low-grade glioma; PNET = primitive neuroectodermal tumor; PROs = patient-reported outcomes; QOL = quality of life; PedQoL = pediatric quality of life; SIB-R = Scale of Independent Behavior, Revised. Table 4. Details regarding quality of life studies of pediatric neoplasms treated with proton beam therapy* Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  Reference  No.  Tumor status  Dose, Gy RBE  QOL/PRO parameters  End points  Conclusions  Criticisms and confounders  Kuhlthau et al., 2012 (41)  142  Primary brain tumors, most commonly PNET (35%), ependymoma (22%), LGG (14%); CSI in 43% PBT only (7%), PBT/surgery (31%), PBT/chemo (9%), trimodality (53%)  ≥45 (96%)  PedQoL: core (functioning), brain tumor (sensorimotor, neurocognitive), cancer modules (psychosocial) Also utilized Wechsler IQ scale, BASC and SIB-R (behavioral), and cross-comparison with scores provided by both parents and children Measured during the first and last weeks of PBT and annually thereafter  QOL rose from start to end of PBT in both CSI and non-CSI, but comparatively less rise from end of PBT to 3 y post-PBT During treatment, lowest scores for school and emotional functioning, anxiety/worry, communication, physical health Worse QOL scores at start statistically correlated with baseline IQ and behavioral tests, PNET/germ cell histology, posterior fossa irradiation, CSI, any chemo receipt, and PBT only/trimodality  QOL increases during PBTNoteworthy clinical factors associated with poorer QOL scores  Heterogeneous population with unclear dosing and likely equally heterogeneous treatment volumes Did not assess baseline home/socioeconomic situation Analyzed PBT dose as a binary (noncontinuous) variable with imbalanced cutoff No association with receipt of anesthesia or lack thereof  Weber et al., 2015 (42)  15  Primary ATRT, resection in 93%, concurrent chemo in 47%  54  PedQoL: physical, emotional, social, school, psychosocial, composite Measured before PBT and compared with measurement at 2 mo  Numerically higher physical, emotional, school scores Numerically lower social score  QOL does not deteriorate at median 33 mo after PBT  Mean (no median) values of QOL scores reported, without statistical comparisons Did not assess baseline home/socioeconomic situation Isolated comparison at just 2 mo post-PBT difficult to interpret regarding long-term QOL  Leiser et al., 2016 (43)  93  Rhabdomyosarcoma, concurrent chemo in 89%, anesthesia in 66%  54  PedQoL measured at baseline and 2 mo post-PBT, and annually thereafter; matched with proxy normal population Questionnaire given to 34 patients  Lower QOL at beginning of PBT vs normal population QOL improves (all domains) at 2 mo post-PBT and continues to 2 y; most notable improvement in first year post-PBT At 2 y, most QOL parameters comparable (or higher) with normal population  QOL increases after PBT  Details regarding surgery missing Excluded patients age < 5 y from QOL analyses Did not assess baseline home/socioeconomic situation Unclear matching of comparison with proxy normal population  * BASC = Behavior Assessment System for Children; ATRT = atypical teratoid rhabdoid tumor; CSI = craniospinal irradiation; Gy RBE = Gray relative biological effectiveness; IQ = intelligence quotient; LGG = low-grade glioma; PNET = primitive neuroectodermal tumor; PROs = patient-reported outcomes; QOL = quality of life; PedQoL = pediatric quality of life; SIB-R = Scale of Independent Behavior, Revised. Two retrospective series from the Paul Scherrer Institute (using pencil-beam scanning PBT) were assessed. The first evaluated PedsQOL results in 15 patients with atypical teratoid/rhabdoid tumor with a median 33-month follow-up (42). The results were similar to those of Kuhlthau and colleagues (41), chiefly that most QOL scores tended to increase as treatment progressed. This was also reflected in another study of rhabdomyosarcoma (43), which included 93 patients, 34 of whom completed the questionnaire (patients younger than age five years were excluded). The scores were matched with those from a proxy “normal” population. The findings supported prior data: QOL improved in all domains starting at the two-month mark and continued to improve throughout the first year after therapy. The authors noted that at the two-year time point, most QOL domains were comparable to or higher than those in the proxy normal population. Discussion The major factors driving implementation and critical evaluation of PBT include relative potential toxicity reductions and improvements in post-treatment QOL decline. To that extent, this is the first systematic review comprehensively and critically reviewing QOL and PRO outcomes following PBT. These findings have notable implications for stakeholders, VBO, and PBT clinical trial design. The available evidence suggests that PBT provides favorable QOL/PRO profiles for select brain, head/neck, lung, and pediatric cancers. A complete discussion of analogous photon studies is beyond the scope of this paper, and substantial heterogeneity characterizes QOL/PRO studies. However, select data from this review will be briefly discussed. As compared with the findings by Shih et al. (28), QOL assessment of a phase III LGG trial of photon RT (without chemotherapy) displayed steady declines in both QOL and mental state questionnaire results (44). Regarding head/neck cancers, for which QOL studies are especially subject to bias from patient and treatment parameters, there were notable QOL declines with more aggressive therapy, which also associated with a greater symptom burden (45). To this extent, the finding of generally lower toxicities for PBT than for photon therapy could be noteworthy and supports the aforementioned (and other) data from MD Anderson indicating lower rates of feeding tube requirements with IMPT (46,47). In locally advanced NSCLC, the results from Wang et al. (30) are consistent in the context of QOL data from a recent phase III dose escalation study showing notable QOL declines in both arms (more so in the high-dose arm) (48). Perhaps most notably, the fact that higher conformality of IMRT was associated with fewer functional assessment score declines than 3DCRT could suggest favorable results for IMPT in subsequent comparisons with IMRT. For pediatric malignancies, QOL results were relatively corroborative, with all three reports suggesting QOL improvements (and not declines) during and after PBT. Although the gradual relief of initial anxiety plays a clear role in these results (highlighting the importance of actively involving child life specialists and/or psychologists), they should also be considered in the context of photon data demonstrating decreases in QOL steadily after RT (49,50). In addition, a retrospective comparison (51) of post-therapy IQ in PBT and photon RT has demonstrated greater decline with photon RT, although the rate of decline was not different between groups. Post-PBT QOL/PRO results for breast and prostate cancers were more modest. There was only one comparative study in breast cancer showing no differences between PBT and photons, which is consistent with prospective data reporting comparable pre- and post-RT QOL with photon RT (52). However, the fact that PBT can be utilized in the APBI setting is important because a recent secondary analysis of phase III data indicated that photon APBI results in higher QOL than conventionally fractionated photon whole-breast RT (53). Prostate cancer is currently the focus of the greatest amount of QOL/PRO data; results for PBT analyzed here in are consistent with findings of retrospectively (54,55) and prospectively collected (56) data displaying no differences in toxicities between PBT and IMRT. However, the finding that stereotactic RT (acknowledging the impact of various dosing regimens) does not produce worse QOL than moderate hypofractionation could be implemented to alter QOL outcomes in future analyses (57). The main conclusions of this review roughly mirror those of the CE of PBT (25) and further illustrate the connection—and, to some extent, interdependence—between QOL and CE. It has been proposed that, based on limited evidence, PBT is cost-effective for pediatric brain neoplasms, locally advanced NSCLC, and some head and neck cancers; it was not cost-effective for prostate cancer and unselected breast cancer cases. Indeed, although these and future QOL/PRO findings will substantially impact the results of future CE analyses, these investigations must utilize QOL data much more frequently than at present (25). More important is the identification of the best methods to integrate QOL into CE studies by relating QOL data to utility values and numeric relationships with cost. This will undoubtedly require major extrapolation (clearly already the basis for CE studies), but the real importance of further data will be when averaging the values from multiple QOL studies instead of complete reliance on single investigations (thus decreasing bias). In addition, QOL (and CE) data are urgently needed for neoplasms for which PBT could offer intuitive advantages (eg, postoperative toxicity/complication reduction in esophageal cancer) (16). One major impact of these and other QOL data on health policy and VBO can be seen in statements made by the American Society of Clinical Oncology (ASCO) Value in Cancer Care Task Force (58). This group initially constructed a quantitative “net health benefit” score associated with a particular intervention, referring to balancing its potential “clinical benefits” with costs. When performing revisions to the initial framework, the Task Force noted a prominent deficiency in both PRO and QOL information. However, the presence of available supportive QOL/PRO information now results in “bonus points” assigned to the net health benefit score. This has been a major step in directly integrating QOL/PRO data with the quantitative metrics of CE. The findings of this systematic review will likely be of interest not only to the Task Force and ASCO’s Quality Oncology Practice Initiative (59) but also to stakeholders using similar metrics to assess the “net health benefits” of PBT. These findings also have implications for ongoing clinical trials (60). As evidence of the increased focus of QOL in these investigations, Table 5 displays currently accruing prospective trials of PBT (registered on clinicaltrials.gov as of March 2017) that have specifically listed QOL as an endpoint. This includes five phase III trials; three studies list QOL/PRO as the primary endpoint. The primary endpoints of most trials are toxicity related, which highlights the need to actively associate these toxicity endpoints with QOL endpoints. Doing so will not only enhance the importance of potential toxicity reductions afforded by PBT for QOL but also serve to more directly integrate QOL metrics into future CE studies. We also encourage clinical trials to include high-quality, validated PRO/QOL assessments prospectively in the most homogeneous populations possible. Emphasis should be placed on global health-related QOL, which provides a unique and important parameter that could be most indicative of PBT efficacy (analogous to the primacy of overall survival as a primary endpoint in many trials). Trials should aim to identify as many sources of potential QOL/PRO bias as possible when performing initial data collection. Many of the studies discussed in this review did not stratify for socioeconomic, marital, employment, or comorbidity status. Organ-specific parameters are equally important, as these will have a major impact on QOL, and consideration should be given to factors like smoking history, prostate volume (only two analyzed studies reported this), prior surgeries, and relevant medications (per Lee et al. [35]). Disease-specific factors are also needed, including but not limited to genomic/molecular data, tumor location (eg, at a high-risk anatomic area), and disease volume. Finally, the majority of studies did not conduct multivariable adjustment of QOL based on treatment modality, and this should also be performed whenever possible. Table 5. Accruing prospective trials of proton therapy, registered on Clinicaltrials.gov as of March 2017, that have specifically listed quality of life as an end point* Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  * CNS = central nervous system; FFF = freedom from failure; IBTR = ipsilateral breast tumor recurrence; LC = local control; MDACC = MD Anderson Cancer Center; MGH = Massachusetts General Hospital; NSCLC = non-small cell lung cancer; Obs = observational; OS = overall survival; PCG = Proton Collaborative Group; PFS = progression-free survival; QOL = quality of life; RTOG = Radiation Therapy Oncology Group; SMC = Samsung Medical Center; TTB = total tumor burden; TUD = Technische Universität Dresden; WHO = World Health Organization. Table 5. Accruing prospective trials of proton therapy, registered on Clinicaltrials.gov as of March 2017, that have specifically listed quality of life as an end point* Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  Clinicaltrials.gov ID  Sponsor  Official study title  Design (phase)  Primary end point  Projected sample size  Estimated accrual period  NCT01973179  TUD  Observational Study to Re-irradiation for Recurrent Head and Neck Cancer  Obs  Late toxicities  50  2015–2023  NCT02736786  Mayo  A Study of Mucosal Sparing Proton Beam Therapy (PBT) in Resected Oropharyngeal Tumors  Obs  LC  67  2016–2020  NCT02452021  Mayo  An Observational Study of Pencil Beam Scanning (PBS) Proton Radiotherapy (RT) as a Component of Trimodality Therapy for Esophageal Cancer  Obs  Grade ≥3 toxicities  30  2015–2019  NCT0111577  MGH  Prospective Assessment of Quality of Life (QOL) in Pediatric Patients Treated With Radiation Therapy for Brain Tumors and Non-CNS Malignancies  Obs  QOL  600  2005–2029  NCT02644993  SMC  Registry for Analysis of Quality of Life, Normal Organ Toxicity and Survival of Pediatric Patients Treated With Proton Therapy  Obs  QOL  400  2015–2025  NCT01858025  MGH  A Pilot Feasibility Study of Definitive Concurrent Chemoradiation With Pencil Beam Scanning Proton Beam in Combination With 5-Fluorouracil and Mitomycin-C for Carcinoma of the Anal Canal  1  Feasibility  25  2013–2019  NCT01117844  Penn  Feasibility and Phase II Study Using Proton Radiation for WHO Grade I-III Meningiomas and Hemangiopericytomas  1–2  Feasibility and safety  50  2010–2017  NCT01045226  Penn  A Phase II Trial of Proton Radiation Therapy of Using Standard Fractionation for Low-and Low-Intermediate Risk Adenocarcinoma of the Prostate  2  Feasibility and acute toxicities  262  2009–2017  NCT00875901  Florida  Hypofractionated, Image-Guided Radiation Therapy With Proton Therapy for Stage I Non-Small Cell Lung Cancer  2  Grade ≥3 toxicities  23  2009–2032  NCT00969111  Florida  Postoperative or Salvage Radiotherapy for Node Negative Prostate Cancer Following Radical Prostatectomy  2  Grade ≥3 toxicities  70  2009–2050  NCT01512589  MDACC  Phase IIB Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer  2  PFS, TTB  180  2012–2019  NCT01811394  Heidelberg  Hypofractionated Ion Irradiation (Protons or Carbon Ions) of Sacrococcygeal Chordoma  2  Feasibility and safety, grade ≥3 toxicities  100  2013–2018  NCT01819831  Loma Linda  A Phase II Trial of Preoperative Proton Therapy in Soft-tissue Sarcomas of the Extremities and Body Wall  2  Late toxicities  51  2013–2022  NCT01758445  PCG  Phase II Study of Postoperative, Cardiac-Sparing Proton Radiotherapy for Patients With Stage II/III, Loco-Regional, Non-Metastatic Breast Cancer Requiring Whole Breast or Chest Wall Irradiation With Lymph Node Irradiation  2  Acute and late toxicities  220  2013–2030  NCT01766297  PCG  Phase II Protocol of Proton Therapy for Partial Breast Irradiation in Early Stage Breast Cancer  2  IBTR, FFF  42  2013–2030  NCT02608762  Chang Gung  Neurobehavioral Outcomes and Quality of Life in Pediatric Patients With Brain or Head/Neck Tumors Receiving Proton or Photon Radiotherapy  2  Wechsler intelligence score  72  2014–2017  NCT02040610  Provision Center  A Phase II Study of Hypofractionated Image Guided Proton Therapy for Low and Intermediate Risk Prostate Cancer  2  Time to biochemical failure  235  2014–2025  NCT02632864  SMC  Feasibility of High Dose PROton Therapy on Unresectable Primary Carcinoma Of Liver: Prospective Phase II Trial  2  2-y OS  66  2015–2019  NCT02797366  Uppsala  Proton Radiotherapy for Primary Central Nervous System Tumours in Adults - a Prospective Swedish Multicentre Study  2  Acute and late toxicities  500  2015–2030  NCT02766686  TUD  Preference-based Comparative Study on Definitive Radiotherapy of Prostate Cancer With Protons in Standard Fractionation and Standard Dosage  2  Grade ≥2 toxicities  146  2016–2023  NCT02731001  TUD  Proton Therapy to Reduce Acute Normal Tissue Toxicity in Locally Advanced Non-small-cell Lung Cancer  2  Acute and late toxicities  98  2016–2024  NCT03018418  Cincinnati  A Prospective Pilot Study to Evaluate the Feasibility of Intensity Modulated Proton Therapy in Reducing Toxicity in Anal Cancer  2  Acute toxicities  20  2017–2023  NCT01617161  MGH  Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer  3  Bowel QOL scores  400  2012–2018  NCT01492972  PCG  Phase III Study of Image Guided Radiation Therapy With or Without Androgen Suppression for Intermediate Risk Adenocarcinoma of the Prostate  3  Morbidity, FFF  192  2012–2021  NCT01993810  RTOG/NRG  Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC  3  OS  560  2014–2020  NCT02640924  Chang Gung  Proton Beam Radiotherapy Versus Switching Control Radiofrequency Ablation for Patients With Medium (>3, ≤5 cm) or Large (>5, ≤7 cm) Treatment-naive Hepatocellular Carcinoma  3  LC  166  2016–2021  NCT0260334  Penn  Pragmatic Randomized Trial of Proton vs Photon Therapy for Patients With Non-Metastatic Breast Cancer: A Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial  3  Cardiovascular events  1720  2016–2030  * CNS = central nervous system; FFF = freedom from failure; IBTR = ipsilateral breast tumor recurrence; LC = local control; MDACC = MD Anderson Cancer Center; MGH = Massachusetts General Hospital; NSCLC = non-small cell lung cancer; Obs = observational; OS = overall survival; PCG = Proton Collaborative Group; PFS = progression-free survival; QOL = quality of life; RTOG = Radiation Therapy Oncology Group; SMC = Samsung Medical Center; TTB = total tumor burden; TUD = Technische Universität Dresden; WHO = World Health Organization. Lastly, recent advances in PBT delivery techniques, such as at the advent of IMPT and volumetric image guidance, could substantially impact the results of future QOL analyses. For instance, it is important to note that comparison of forward-planned passively scattered PBT (which comprised the dominant technique in the studies discussed herein) is most analogous to photon 3D-CRT. IMRT would more appropriately be compared with inverse-planned IMPT (which, owing to its newer implementation in clinical practice, has much more limited QOL/PRO data available to date. Therefore, existing literature comparing advanced photon techniques with first-generation proton techniques might be inherently biased against proton therapy. There are also biases regarding the learning curve of new technologies such as PBT as compared to more established photon techniques such as IMRT. Additionally, in nonrandomized trials, there are unavoidable selection biases regarding the use of protons vs photons to treat a given patient, such as proximity to organs at risk or ease/difficulty in meeting dose constraints with protons vs photons. Furthermore, in both randomized and nonrandomized trials, insurance status (eg, Medicare is more likely to pay for elderly patients’ PBT, vs other commercial insurances less likely to pay in the non-Medicare population) may play a factor in who receives which type of radiotherapy modality, and this may also have served to bias existing studies reporting on QOL/PROs. Limitations of this work, similar to CE analyses, are that there are no “perfectly conducted” QOL/PRO studies. These parameters are inherently subjective and are influenced by numerous factors, including inherent psychosocial, behavioral, and cultural attitudes. It is impossible for investigations to account for all of these variables, acknowledging that confounding factors will always be present (at the very least, potentially biased in PBT patient selection regarding those with the means to travel longer distances to PBT facilities) (Tables 1–4). Rather, also similar to CE work, the goal of a QOL/PRO investigation is to provide a rough comparison between groups (or observation of a cohort) so that, ideally, further work can be corroborated by additional research. QOL/PRO data are thus important to recognize as constituting a dynamically changing entity that can be substantially influenced by the quality and volume of further additional data (including patient selection) as they are published. Herein, although the overall quality and quantity of data available on QOL and PBT remain relatively low, thus permitting few robust conclusions, there are salient “lessons to be learned” that can allow for sharper and more insightful interpretation of QOL/PRO analyses of active and planned clinical trials. Taken together, the lessons for ongoing clinical trials involve performing high-quality, thorough QOL/PRO evaluations. Doing so may allow for delineation of patient subpopulations that proportionally receive greater QOL (and CE) benefits (as QOL is not a binary term); moreover, it will increase the applicability, impact, validity, and reliability of the data on both future CE analyses and VBO as a whole. This is critical to consider, especially in an ever-changing medico-economic climate. Notes There were no sponsors or funders for this study. All authors declare that conflicts of interest do not exist. References 1 Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. 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JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Oct 9, 2017

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